2-hydroxy-3-phenoxy-propyl-substituted piperazines, their preparation and use

ABSTRACT

PCT No. PCT/EP89/01058 Sec. 371 Date Mar. 18, 1991 Sec. 102(e) Date Mar. 18, 1991 PCT Filed Sep. 12, 1989 PCT Pub. No. WO90/03371 PCT Pub. Date Apr. 5, 1990.2-Hydroxy-3-phenoxy-propyl-substituted piperazines of the formula I    &lt;IMAGE&gt;  I  in which R1-R5, Y, m and n have the meaning indicated in the description, and the preparation thereof are described. The novel compounds are suitable for the therapy of oxygen deficiency diseases of the brain.

DESCRIPTION

The invention relates to 2-hydroxy-3-phenoxypropyl-substituted piperazines and homopiperazines, processes for the preparation thereof and the use thereof as drugs.

Numerous piperazines of various types have already been disclosed. Thus, for example, flunarizine and lidoflazine from the benzhydryl- and diarylbutylpiperazine series have been disclosed as therapeutics for cardiovascular and cerebrovascular disorders. Their mode of action is based on inhibition of the influx of calcium into the cell.

This mechanism of action also applies to the ω-phenoxy-alkyl-piperazines described in DE-A 3.600.390. The therapeutic aim of these compounds is, just like that of the benzhydryl-phenylalkanol-substituted piperazines described in DE-A 3.326.148, to treat disorders of the cerebral circulation.

N-Arylpiperazinealkanamides with diarylbutyl substituents on the piperazine ring (cf. EP-A 68544) improve the blood supply to the heart and protect it from the consequences of an ischemia, anoxia or hypoxia.

3-Aryloxy-2-propanol derivatives of phenylpiperazine have also been disclosed, but they display no calcium-antagonistic or antihypoxic effects (Arzneim. Forsch. (1978) 28 241-246).

It has now been found that 2-hydroxy-3-phenoxypropyl-substituted piperazines or homopiperazines of the formula I ##STR2## in which R¹ and R² denote hydrogen, fluorine or chlorine atoms, methoxy, methyl or trifluoromethyl groups,

R³, R⁴ and R⁵ denote hydrogen, fluorine or chlorine atoms, methyl, trifluoromethyl, cyano or nitro groups or a saturated or unsaturated alkoxy group with up to 3 C atoms,

Y denotes an oxygen or sulfur atom,

m denotes 1, 2 or 3 and

n denotes 2 or 3,

are strong calcium antagonists which have a pronounced cerebral antihypoxic effect and which significantly improve the regional blood supply to the brain.

Thus the compounds according to the invention appear to be suitable for the therapy of cardiovascular disorders in general and in particular for treating acute and chronic oxygen deficiency states of the brain. By this are meant acute hypoxic or ischemic states occurring, for example, following cerebral infarct, craniocerebral trauma or vasospasms and following cardiovascular failure, e.g. associated with cardiac arrest, cardiac arrhythmias or circulatory failure. Examples of relevant syndromes with chronic oxygen deficiency states are: transient ischemic attacks (TIAs) and prolonged reversible ischemic neurological deficits (PRINDs), as well as multiinfarct dementia and atherosclerotic dementia, besides migraine and epilepsies.

Suitable physically tolerated acids are: inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid or organic acids such as tartaric acid, lactic acid, malic acid, citric acid, maleic acid, fumaric acid, oxalic acid, acetic acid, gluconic acid or mucic acid.

In the formula I, R¹ and R² are preferably hydrogen, fluorine or chlorine atoms, R³ and R⁴ are preferably hydrogen atoms, while R⁵ is, in particular, a fluorine or chlorine atom. n is preferably 2 and m is preferably 2 or 3. Y is, in particular, an oxygen atom. The substituents R¹, R² and R⁵ are, in particular, located in the 3 or 4 position of the phenyl rings. The 4 positions are preferred.

The compounds of the formula I have a center of chirality in the structural element of the aryloxypropanol. They therefore exist in the form of optical antipodes (enantiomers). The racemates can be obtained by conventional methods by salt formation with chiral auxiliary components such as dibenzoyltartaric acid, fractional crystallization and subsequent liberation of the bases from the salts or else by synthesis from suitable chiral precursors.

The invention also relates to processes for preparing the compounds of the formula I, which comprise reacting either

a) a compound of the formula II ##STR3## in which R¹, R², m and n have the stated meaning, with an epoxide of the formula III ##STR4## in which Y, R³, R⁴ and R⁵ have the stated meaning, or b) a compound of the formula IV ##STR5## in which Y, R³, R⁴, R⁵ and n have the stated meaning, with a compound of the formula V ##STR6## where R¹, R², and m have the stated meaning, and X denotes a reactive acid residue. The compounds obtained in this way can then be converted with physiologically tolerated acids into their salts.

The reaction, which is known per se, of epoxides of the formula III with secondary amines of the formula II is expediently carried out in a solvent such as acetonitrile, dimethylformamide, tetrahydrofuran or a lower alcohol, preferably methanol or ethanol, at elevated temperatures (30°-120° C.), preferably at the boiling points of the solvent.

Process b) is preferably carried out in a polar organic solvent such as alcohols, e.g. methanol, ethanol, isopropanol or a lower ketone, preferably acetone, methyl ethyl ketone or methyl isobutyl ketone or in dimethylformamide. Dimethyl sulfoxide, acetonitrile, where appropriate also in a hydrocarbon such as toluene, advantageously in the presence of an auxiliary base to trap the acid which is formed, such as, for example, sodium carbonate, potassium carbonate, calcium carbonate, triethylamine or pyridine at elevated temperature, preferably between 20° and 120° C. Suitable reactive acid residues X are chlorine, bromine or iodine atoms and sulfonic acid groups, preferably methanesulfonyl, benzenesulfonyl, p-toluenesulfonyl or trifluoromethanesulfonyl radicals.

The starting compounds of the formula II to V are known from the literature or can be prepared analogously in a manner known per se. Thus, reaction of optically active (R)- or (S)-epichlorohydrin with phenols or thiophenols of the formula VI ##STR7## in which Y, R³, R⁴ and R⁵ have the stated meanings, results in optically active epoxides of the formula III which can be reacted with the compounds of the formula II to give optically active compounds of the formula I.

The compounds according to the invention can be administered in a customary manner orally, rectally or parenterally (subcutaneously, intravenously, intramuscularly, transdermally). Administration can also take place through the nasopharyngeal space with vapors or sprays.

The dosage depends on the age, condition and weight of the patient and on the mode of administration. As a rule, the daily dose of active substance is between about 0.1 and 20 mg/kg of body weight on oral administration and between about 0.01 and 2 mg/kg of body weight on parenteral administration. In the normal case, satisfactory results are achieved with daily doses of 10-100 mg orally and 1-10 mg parenterally.

The novel compounds can be used solid or liquid in the conventional pharmaceutical administration forms, e.g. as tablets, film-coated tablets, capsules, powders, granules, sugar-coated tablets, suppositories, solutions, ointments, creams, sprays or transdermal therapeutic systems. These are prepared in a conventional manner. This may entail the active substances being processed with the conventional pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants antioxidants and/or propellant gases (cf. H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The administration forms obtained in this way normally contain the active substance in an amount of from 1 to 75% by weight.

EXAMPLES

1. 1-[4,4-bis(4-Fluorophenyl)butyl]-4-[2-hydroxy-3(4-chlorophenoxy)propyl]piperazine

6.6 g (0.02 mol) of 1-[4,4-bis(4-fluorophenyl)]-butylpiperazine and 3.7 g (0.02 mol ) of 3-(4-chlorophenoxy)-1,2-epoxypropane in 100 ml of ethanol were heated to boiling under reflux for 2 h. After cooling, the solvent was removed by distillation under reduced pressure. Ethereal hydrochloric acid added to the oily residue, the precipitate filtered off with suction and the product recrystallized with isopropanol/water. Yield: 5.2 g di-hydrochloride C₂₉ H₃₃ ClF₂ N₂ O₂.2HCl, melting point 205°-211° C.

The following were prepared analogously:

2. 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3(4-fluorophenoxy)propyl]piperazine, di-hydrochloride C₂₉ H₃₃ F₃ N₂ O₂.2HCl, melting point 225°-227° C.,

3. 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-phenoxypropyl]piperazine,di-hydrochloride C₂₉ H₃₄ F₂ N₂ O₂ . 2HCl, melting point 237°-240° C.

4. 1-[4,4-diphenylbutyl]-4-[2-hydroxy-3-phenoxypropyl]-piperazine, di-hydrochloride C₂₉ H₃₆ N₂ O₂.2HCl, melting point 237°-242° C.

5. 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazine, di-hydrochloride C₃₀ H₃₆ F₂ N₂ O₂.2HCl, melting point 199°-201° C.

6. 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(2-allyloxyphenoxy)propyl]piperazine, di-hydrochloride C₃₂ H₃₈ F₂ N₂ O₃.2HCl, melting point 154°-156° C.

7. 1-[3,3-diphenylpropyl]-4-[2-hydroxy-3-phenoxypropyl]piperazine, di-hydrochloride C₂₈ H₃₄ N₂ O₂.2HCl, melting point 242°-250° C.

8. 1-[3,3-diphenylpropyl]-4-[2-hydroxy-3(4-chlorophenoxy)propyl]piperazine, di-hydrochloride C₂₈ H₃₃ ClN₂ O₂.2HCl, melting point 235°-240° C.

9. 1-[2,2-diphenylethyl]-4-[2-hydroxy-3-(4-chlorophenoxy)propyl]piperazine, di-hydrochloride C₂₇ H₂₉ Cl₃ N₂ O₃.2HCl, melting point 240°-245° C.

10. 1-[4,4-bis(4-trifluoromethylphenyl)butyl]-4-[2-hydroxy-3(4-fluorophenoxy)propyl]piperazine, di-hydrochloride C₃₁ H₃₁ F₇ N₂ O₂.2HCl, melting point 195°-198° C.

11. 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3(3-trifluoromethylphenoxy)propyl]piperazine, di-hydrochloride C₃₀ H₃₃ F₅ N₂ O₂ . 2HCl, melting point 180°-185° C.

12. 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(3,4-dichlorophenoxy)propyl]piperazine, di-hydrochloride C₂₉ H₃₂ Cl₂ F₂ N₂ O₂.2HCl, melting point 202°-209° C.

13. 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(c-chlorophenoxy)propyl]piperazine, di-hydrochloride C₂₉ H₃₃ ClF₂ N₂ O₂.2HCl, melting point 205°-211° C.

14. 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3(4-methylphenoxy)propyl]piperazine, di-hydrochloride C₃₀ H₃₆ F₂ N₂ O₂.2HCl, melting point 229°-235° C. 15. 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3(3,4-dimethylphenoxy)propyl]piperazine, di-hydrochloride C₃₁ H₃₈ F₂ N₂ O₂.2HCl, melting point 224°-229° C.

16. 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(4-nitrophenoxy)propyl]piperazine, di-hydrochloride C₂₉ H₃₃ F₃ N₃ O₄.2HCl, melting point 217°-224° C.

17. 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(2-cyanophenoxy)propyl]piperazine, di-hydrochloride C₃₀ H₃₃ F₂ N₃ O₂ . 2HCl, melting point 216°-224° C.

18. 1-[4,4-bis(4-trifluoromethylphenyl)butyl]-4-[2 -hydroxy-3-(3-chlorophenoxy)propyl]piperazine, dihydrochloride C₃₁ H₃₁ ClF₆ N₂ O₂.2HCl, melting point 190°-195° C.,

19. 1-[4,4-bis(4-trifluoromethylphenyl)butyl]-4-[2-hydroxy-3-(3,4-dichlorophenoxy)propyl]piperazine, di-hydrochloride C₃₁ H₃₀ Cl₂ F₆ N₂ O₂.2HCl, melting point 190°-197° C.,

20. 1-[4,4-bis(4-trifluoromethylphenyl)butyl]-4-[2-hydroxy-3-(3-trifluoromethylphenoxy)propyl]piperazine, di-hydrochloride C₃₂ H₃₁ F₉ N₂ O₂.2HCl, melting point 193°-200° C.,

21. 1-[4,4-bis(4-trifluoromethylphenyl)butyl]-4-[2-hydroxy-3-(4-nitrophenoxy)propyl]piperazine, di-hydrochloride C₃₁ H₃₁ F₆ N₃ O₄.2HCl, melting point 124°-127° C. (amorphous),

22. 1-[4,4-diphenylbutyl]-4-[2-hydroxy-3-(4-fluorophenoxy)propyl]piperazine, di-hydrochloride C₂₉ H₃₅ FN₂ O₂.2HCl, melting point 198°-201° C.

23. 1-[4,4-diphenylbutyl]-4-[2-hydroxy-3-(3,4-dichlorophenoxy)propyl]piperazine, di-hydrochloride C₂₉ H₃₄ Cl₂ N₂ O₂.2HCl, melting point 200°-205° C.

24. 1-[4,4-bis(4-methylphenyl)butyl]-4-[2-hydroxy-3-(4-fluorophenoxy)propyl]piperazine, di-hydrochloride C₃₁ H₃₉ FN₂ O₂.2HCl, melting point 192°-196° C.

25. 1-[4,4-bis(4-methoxyphenyl)butyl]-4-[2-hydroxy-3-phenoxypropyl]piperazine, di-hydrochloride C₃₁ H₄₀ N₂ O₂.2HCl, melting point 214°-216° C.

26. 1-[4,4-bis(4-methoxyphenyl)butyl]-4-[2-hydroxy-3-(3.4.5-trimethoxyphenoxy)propyl]piperazine, dihydrochloride C₃₄ H₄₆ N₂ O₇.2HCl, melting point 190°-193° C.

27. 1-[4,4-bis(3-fluorophenyl)butyl]-4-[2-hydroxy-3-(4-fluorophenoxy)propyl]piperazine, di-hydrochloride C₂₄ H₃₃ F₃ N₂ O₂.2HCl, melting point 222°-225° C.

28. 1-[4,4-bis(4-chlorophenyl)butyl]-4-[2-hydroxy-3-(4 -chlorophenoxy)propyl]piperazine, di-hydrochloride C₂₉ H₃₃ Cl₃ N₂ O₂.2HCl, melting point 190°-196° C.

The following were obtained by reacting the enantiomers 3-(4-fluorophenoxy)-1,2-epoxy-propanes (obtained by synthesis from 4-fluorophenol and (R)- or (S)-epichlorohydrin) with 1-[4,4-bis(4-fluorophenyl)butyl]piperazine in analogy to Example 1:

29. (-)-1[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3(4-fluorophenoxy)propyl]piperazine, dihydrochloride C₂₉ H₃₃ F₃ N₂ O₂.2HCl, melting point 208°-216° C., [α]₅₈₉ mm²⁰ =-9.4° (methanol, 10 mg/ml),

30. (+)-1[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3(4-fluorophenoxy)propyl]piperazine, di-hydrochloride C₂₉ H₃₃ F₃ N₂ O₂.2HCl, melting point 208°-216° C., [α]₅₈₉ mm²⁰ =-9.4° (methanol, 10 mg/ml),

31. (-)-1(3,3-diphenylpropyl)-3-[2-hydroxy-3(4-fluorophenoxy)propyl]piperazine, di-hydrochloride C₂₈ H₃₃ FN₂ O₂.2HCl, melting point 230°-233° C., [α]_(589mm) ²⁰ =-10.9° (c=15 mg/ml),

32. (+)-1(3,3-diphenylpropyl)-3-[2-hydroxy-3(4-fluorophenoxy)propyl]piperazine, di-hydrochloride C₂₈ H₃₃ FN₂ O₂.2HCl, melting point 230°-233° C., [α]₅₈₉ mm²⁰ =+10.6° (methanol=15 mg/ml),

33. 1-[4,4-bis(4-fluorophenyl)butyl]-4-(2-hydroxy-3(4-fluorophenoxy)propyl]homopiperazine

5.9 g (0.022 mol) of 1-[2-hydroxy-3-(4-fluorophenoxy)propyl]homopiperazine and 6.2 g (0.022 mol) of 4,4-bis(4-fluorophenyl)butyl chloride were dissolved with 3.2 g of calcium carbonate in 100 ml of toluene and heated to boiling under reflux with stirring for 2.5 h. After cooling, filtration with suction was carried out, the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography. (Silica gel, eluent methylene chloride with 4% methanol). Yield 4.0 g, oxalate, C₃₀ H₃₅ F₃ N₂ O₂.2 C₂ H₂ O₄, melting point 160°-165° C.

34. Reaction in analogy to Example 1 of 1-[4,4-bis(4-fluorophenyl)butyl]piperazine with 3-(4-fluorothiophenoxy)1,2-epoxypropane (obtained by reaction of 4-fluoro-thiophenol with epichlorohydrin)-resulted in 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(4-fluoro-thiophenoxy)propyl]piperazine, di-hydrochloride C₂₉ H₃₃ F₃ N₂ OS.2HCl, melting point 212°-215° C.

The following was prepared in the same way:

35. 1-(3,3-diphenylpropyl)-3-[(2-hydroxy-3-thiophenoxy)propyl]piperazine, di-hydrochloride C₂₈ H₃₄ N₂ OS.2HCl, melting point 236°-240° C.

The effect of the novel substances was measured as follows:

1. Protection from acute cerebral hypoxia

Female mice (weight 22-28 g) were placed in a glass tube (diameter 6 cm) through which was passed a mixture of 3.5 parts of oxygen and 96.5 parts of nitrogen. Untreated control animals survived 138 sec. on average in a glass tube of this type. The dose of active substances which, after intraperitoneal administration thereof, increases the survival time of the animals by 50% was determined.

2. Protection from global cerebral ischemia

Female mice (weight 24-27 g) received the active substance intraperitoneally before administration of 0.1 ml of an 80% strength solution (g/l) of MgCl₂.6H₂ O. Untreated control animals survive 24 sec. on average after administration of MgCl₂. The dose of active substances which increases the survival time of the animals by 50% compared with placebo-treated animals was determined.

3. Affinity of the test substances to the calcium channel.

The affinity of the test substances to the calcium channel was determined by inhibition of the specific (S)-³ H-devapamil binding to guinea-pig skeletal muscle membranes (FEBS Lett. 176, 371 (1984)). For this, the membranes were incubated with a fixed concentration of 1 nM (S)-³ H-devapamil and increasing concentrations of test substance in 50 mM tris-HCl/0.1 mM phenylmethylsulfonyl fluoride, (pH 7.4) at 20° C. for 60 minutes. The non-specific binding was determined using 10⁻⁶ M (S)-devapamil. The mixtures were then filtered through glass fiber filters, and the amount of (S)-³ H-devapamil retained on the filter was determined by liquid scintillation measurement. The Ki values were determined by non-linear regression analysis.

The table which follows shows the results obtained in the abovementioned tests. The comparison substances used were the substances flunarizine and lidoflazine, which are active ingredients of commercial products.

                  TABLE                                                            ______________________________________                                                    Test 1      Test 2                                                  Substance of                                                                              mg/kg i.p.  mg/kg i.p.                                                                               Test 3                                        Example No.                                                                               ED 50%      ED 50%    Ki (nM)                                       ______________________________________                                          1         11          27        8                                              2         11          20        9.1                                            3         10          13        8                                              4         6.6         8.6       18                                             7         4.6         10        280                                            8         5.0         13        160                                            9         7.3         12        30                                            11         4.9         46        8                                             12         4.7         45        16                                            13         6.9         39        10                                            16         5.5         38        11                                            17         16          27        10                                            22         6.0         8.8       15                                            23         8.6         41        22                                            24         23          40        12                                            27         14          29        22                                            29         1.6         13        9                                             30         4.0         17        10                                            31         4.1         9.3       149                                           32         4.2         9.5       249                                           33         4.8         31        13                                            34         9.0         28        9                                             35         8.7         14        159                                           flunarizine                                                                               >100        26.5      288                                           lidoflazine                                                                               10          >46       20                                            ______________________________________                                     

We claim:
 1. A piperazine of the formula I ##STR8## in which R¹ and R² denote hydrogen, fluorine or chlorine atoms,R³, R⁴ and R⁵ denote hydrogen, fluorine or chlorine atoms, Y denotes an oxygen or sulfur atom, m denotes 3 and n denotes 2, or the salts thereof with physiologically tolerated acids.
 2. The piperazine of claim 1 which is 1-[4,4-bis(4-Fluorophenyl)butyl]-4-[2-hydroxy-3-(4-fluorophenoxy)propyl]piperazine.
 3. The piperazine of claim 1 which is (-)-1-[4,4-bis(4-Fluorophenyl)butyl]-4-[2-hydroxy-3-[4-fluorophenoxy)propyl]piperazine.
 4. The piperazine of claim 1 which is (+)-1-[4,4-bis(4-Fluorophenyl)butyl]-4-[2-hydroxy-3-(4-fluorophenoxy)propyl]piperazine.
 5. A pharmaceutical composition for the treatment of oxygen deficiency states of the brain which comprises an effective amount of a piperazine of the formula I of claim
 1. 6. A method for treating patients with oxygen deficiency states of the brain, which comprises administering to the patients an effective amount of a compound of the formula I as claimed in claim
 1. 